Abstract 5023: NSCLC PDX model for the evaluation of immuno-oncological treatment strategies

Abstract

Abstract Patient-derived tumor xenografts (PDX) have played a major role in the development of new cancer therapies and their strengths and weaknesses have gradually been elucidated. One major drawback of PDX is the lack of an immunological competent host. To overcome this hurdle we supplemented NSG/NOG mice with human hematopoietic stem cells (HSC) and subsequently examined growth characteristics of the non-small cell lung cancer (NSCLC) PDX model LXFA 923 in these mice. In parallel we monitored the presence of human and murine immune cells in different organs of the mouse. HSC (2×106) cells were isolated from healthy donors and injected intravenously into sub-lethally irradiated NSG or NOG mice (n = 43 mice in 3 ind. exp.). After 8 weeks LXFA 923 was transplanted subcutaneously (s.c.) into the pretreated mice. Murine peripheral blood was examined by flow cytometry for common murine and human markers expressed on immune cells (hCD14, mCD14, hCD3, mCD3, hCD56, mCD56, hCD19) once weekly. At the end of the experiment tumors and organs were analyzed for human cancer (CD44, CD133, CDCP1, CD166, CD24) and immune cell markers (hCD14, hCD3, hCD56, hCD19) by flow cytometry. Tumors and organs were additionally histologically and immunohistochemically examined. Growth of the implanted tumors was monitored by caliper measurement. Mice bearing only the subcutaneous PDX or the HSC served as control groups. Stable engraftment of human immune cells in immune-compromized mice was successfully achieved. Human immune cells expressing T-, B-, NK- and stem cell markers could be detected in different compartments (bone marrow, peripheral blood and spleen) of the tumor-bearing as well as non-tumor bearing mice. Furthermore, infiltrates of human monocytes (CD14+) as well as T cells (CD3+) could be detected in s.c. implanted tumor tissue. Implantation of LXFA 923 did not influence the proliferation of human immune cells in recipient mice. Growth behavior of the s.c. implanted PDX was not affected by the engraftment of HSC in the murine host. The histological architecture of LXFA 923 was similar when implanted s.c. in humanized or immunodeficient mice and it still closely resembles the patient donor material. In conclusion, our investigations validate the analysis of PDX in mice engrafted with human immune cells, as it enables the interaction of tumor cells with human immune cells as well as with murine stroma to be investigated. This preclinical PDX based in vivo platform provides a further step to support the development of new drugs targeting the host immune response. Citation Format: Eva Oswald, Kerstin Klingner, Dorothee Lenhard, Gabriele Niedermann, Julia B. Schüler. NSCLC PDX model for the evaluation of immuno-oncological treatment strategies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5023. doi:10.1158/1538-7445.AM2015-5023